During the previous project period, we have pioneered the identification of signal transduction pathways that control specialized properties of skeletal myofibers as a function of changing patterns of neuromuscular activity (e.g. exercise training). Using gain-of-function approaches in transgenic mice, we have demonstrated that it is possible to evoke training-like responses in muscles of sedentary animals, including changes in expression of contractile protein isoforms, enzymes of intermediary metabolism, and other proteins that distinguish one myofiber subtype from another. These findings suggest that it should be possible to translate this basic knowledge into novel therapies to benefit human health. A logical next step will be to identify which of the several signaling pathways known to control myofiber specialization most effectively recapitulates salutary effects of exercise training on medically important outcomes such as enhanced exercise capacity or prevention of diabetes. Such information will focus attention on the most attractive targets for drug discovery. To these ends, we propose the following specific aims: (1) to determine which of the specific signaling pathways known to be activated by endurance training in skeletal muscles are most potent in promoting metabolic consequences that underlie medically important physiological outcomes (increased endurance exercise capacity and reversal of , diet-induced glucose intolerance); (2) to identify additional signaling molecules and pathways that participate in adaptive responses to endurance training that promote metabolic consequences serving to augment exercise capacity and reverse insulin resistance induced by diet. Our proposed studies are novel within the field of muscle biology, and the findings will deepen our understanding of the molecular basis for health-promoting effects of exercise training to augment functional capacity and to prevent obesity, Type II diabetes and cardiovascular disease. This work will inform and focus efforts to identify small molecules potentially useful as drugs to mimic or enhance favorable effects of exercise.